Human papillomaviruses (HPV) are members of the Papillomaviridae family of DNA viruses. More than 100 HPV types have been identified so far, over 30 of which infect the genital area. Genital HPV infections are estimated to be the most common sexually transmitted infections (STI). Although the majority of infections cause no symptoms and are self-limiting, genital HPV have become a major public health concern because persistent infection with certain types can cause cervical cancer which kills about 250,000 women worldwide each year. Genital HPVs are classified by their association with cervical cancer. Infection with low-risk types (primarily types 6 and 11) can cause benign or low-grade cervical cell changes and genital warts and are not associated with cervical cancer. Infection with high-risk types (primarily types 16, 18, 31, and 45) can cause low-grade and high-grade cervical cell abnormalities that are precursors to cancer and cervical cancer.
Cervical cancer is relatively uncommon in countries where widespread cervical Pap testing detects precancerous lesions before they can develop into cancer. In many developing countries where screening activities are limited, cervical cancer is the most common cancer in women. HPVs have also been implicated in a substantial fraction of other anogenital cancers at other anatomic sites, including the vulva, vagina, penis and anus.
No direct antiviral cure or treatment is currently available. Regular Papanicolau screening (Pap test), followed by ablative treatment of any abnormalities when detected, prevents HPV progression to cervical cancer.
Recently, highly effective vaccines were approved for interventions to prevent infection by four HPV types which together cause about 70% of cervical cancers (HPV-16 and HPV-18) and 90% of genital warts (HPV-6 and HPV-11) worldwide. The vaccine protects women only from contracting HPV infections of the types they have not yet encountered, and it should be administered to young women before they become sexually active in order to ensure maximum benefit. However, vaccinated women may remain exposed to the risk of becoming infected with some types of high-risk HPV that can cause cervical cancer but are not targeted by the current vaccine. Moreover, the vaccine is expensive and its cost could be prohibitive, especially for women in underdeveloped countries.
Within this scenario, a topical microbicide that could block the full spectrum of genital HPV infections at the portal of entry would provide a useful complement to vaccination programs.
Herpes simplex viruses (HSV) type 1 and 2 (HSV-1 and HSV-2) are closely related pathogens of the Herpesviridae family of DNA viruses. Both cause a lifelong, latent infection for which there is no cure or available effective vaccine. HSV-1 is usually transmitted via non-sexual contact and is generally clinically associated with oro-labial infection, whereas HSV-2 is typically transmitted sexually and infects anogenital sites. However, HSV-1 and HSV-2 are both capable of infecting mucosal sites, irrespective of their anatomic localization, and can produce clinically indistinguishable lesions. RSV infection causes various forms of disease, from lesions on the lips, eyes or genitalia to encephalitis or disseminated disease. The seroprevalence of HSV-1 spreads gradually from childhood, reaching up to 70-80% of the adult population worldwide, whereas HSV-2 seroprevalence rises after initiation of sexual activity and increases through adulthood (range, 5-25%). Women are more susceptible to HSV-2 infection than men. HSV-2 infection is a major public health problem and the most frequent cause of recurrent genital ulcer disease, with a high seroprevalence among young adults. Many infected individuals, often unaware of their serostatus, shed HSV asymptomatically and so may sexually transmit the infection.
HSV infection can result in a number of severe complications particularly in neonates, often resulting in disseminated disease with high morbidity and mortality, as well as stromal keratitis, a corneal infection that can lead to blindness. HSV infection also produces serious complications in the immunocompromised in whom severe recurrence and occasionally disseminated infection more readily occurs.
A notoriously close relationship exists between HSV and HIV infection: HIV infection increases both the risk and the morbidity of HSV infection, while genital ulcer disease, primarily associated with HSV-2, clearly enhances transmission of HIV-1 infection.
Strategies that can prevent HSV infection are expected to reduce rates of sexual HIV transmission and vice versa.
Acyclovir, a nucleoside analogue, is the antiviral drug of choice for treating HSV infection in the immunocompetent and the immunosuppressed because of its efficacy and lack of toxicity. But like other anti-herpetic agents for treating HSV infection, acyclovir fails to eradicate the virus from infected cells and to prevent reinfection/reactivation of HSV because, although it reduces the production of new viral particles, it cannot counteract early HSV infection.
Inhibitors of the early phase of HSV infection, including viral attachment and entry, are still lacking.
New therapeutic approaches are therefore highly desirable.